Temozolomide powder formulation

Abstract

The present invention relates to a solid pharmaceutical composition of temozolomide that has good and consistent flowability as a powder and taste masking and is readily dispersible in an aqueous solution suitable for oral administration, e.g., as a dry sprinkle. This permits patients and healthcare workers to accurately measure doses and safely dispense the drug.

We claim: 
     
       1. A method of administering temozolomide comprising orally administering a temozolomide powder with a separate drink of water, wherein the temozolomide powder is readily dispersible in an aqueous solution suitable for oral administration and the temozolomide powder comprises:
 (a) granules of temozolomide and one or more emulsifiers, the granules coated with a pH dependent coating composition comprising a pH dependent coating material; and 
 (b) a dispersant, 
 wherein at least 80% of the temozolomide powder dissolves within 30 minutes when tested according to USP I dissolution test (basket) in 900 mL of 0.1 N HCl at 37° C.±0.5° C. and a speed of 100 rpm. 
 
     
     
       2. A method of administering temozolomide comprising orally administering a solution of a temozolomide powder, wherein the temozolomide powder is readily dispersible in an aqueous medium and the temozolomide powder comprises:
 (a) granules comprising (i) from about 50 to about 75% by weight of temozolimide, (ii) from about 25 to about 50% by weight of emulsifier, and (iii) optionally, from about 0.1 to about 2.5% of an adsorbent, where the weight percentages are based on the total weight of the uncoated granules; 
 (b) a coating composition on the granules comprising (i) from about 40 to about 80% by weight of a pH-dependent coating material, (ii) from about 20 to about 60% by weight of glidant, and (iii) from about 0.1 to about 8% by weight of plasticizer, where the weight percentages are based on the total weight of the coating composition; 
 (c) from about 50 to about 75% by weight of dispersant; and 
 (d) optionally, one or more of sweeteners, glidants, lubricants and flavours, based upon 100% total weight of temozolimide powder. 
 
     
     
       3. A method of administering temozolomide comprising orally administering a temozolomide powder with a separate drink of water, wherein the temozolomide powder is readily dispersible in an aqueous medium and the temozolomide powder comprises:
 (a) granules comprising (i) from about 50 to about 75% by weight of temozolimide, (ii) from about 25 to about 50% by weight of emulsifier, and (iii) optionally, from about 0.1 to about 2.5% of an adsorbent, where the weight percentages are based on the total weight of the uncoated granules; 
 (b) a coating composition on the granules comprising (i) from about 40 to about 80% by weight of a pH-dependent coating material, (ii) from about 20 to about 60% by weight of glidant, and (iii) from about 0.1 to about 8% by weight of plasticizer, where the weight percentages are based on the total weight of the coating composition; 
 (c) from about 50 to about 75% by weight of dispersant; and 
 (d) optionally, one or more of sweeteners, glidants, lubricants and flavours, based upon 100% total weight of temozolimide powder. 
 
     
     
       4. The method of  claim 1 , wherein the emulsifiers are selected from sodium lauryl sulfate, poloxamer, saturated polyglycolized glyceride, labrasol, polysorbates, sorbitan esters, cremophor PEG-60 hydrogenated castor oil, PEG-40 hydrogenated castor oil, sodium lauryl glutamate, disodium cocoamphodiacetate, tyloxapol, lauroyl macrogol-6 glycerides, oleoyl macrogol-6 glycerides, linoleoyl macrogol-6 glycerides, propylene glycol monocaprylate, propylene glycol monocaprylate, propylene glycol monolaurate, polyglyceryl-3 dioleate, polyglyceryl-3 dioleate oleate, triglycerides medium-chain, propylene glycol dicaprylocaprate, diethylene glycol monoethyl ether, behenoyl polyoxyl-8 glycerides or PEGylated glyceryl behenate, glyceryl behenate, glyceryl dipalmitostearate, glyceryl behenate E471, diethylene glycol monoethyl ether, octylphenol ethoxylate, sodium deoxycholate, and a mixture of (i) refined soybean oil, (ii) glyceryl distearate and (iii) polyglyceryl-3 dioleate. 
     
     
       5. The method of  claim 1 , wherein the emulsifier is stearoyl macrogol-32 glycerides. 
     
     
       6. The method of  claim 1 , wherein the weight ratio of temozolomide and emulsifier is from about 1:1 to about 3:1. 
     
     
       7. The method of  claim 1 , wherein the granules further comprise an adsorbent. 
     
     
       8. The method of  claim 7 , wherein the adsorbent is colloidal silicon dioxide. 
     
     
       9. The method of  claim 1 , wherein the composition is in the form of a powder. 
     
     
       10. The method of  claim 9 , wherein the powder has a d 50  of no more than 420 microns. 
     
     
       11. The method of  claim 1 , wherein the pH dependent coating composition is porous to water. 
     
     
       12. The method of  claim 1 , wherein the pH dependent coating material comprises an amino methacrylate copolymer. 
     
     
       13. The method of  claim 1 , wherein at least 80% of the solid pharmaceutical composition dissolves within 30 minutes when tested according to USP I dissolution test (basket) in 900 mL of an water at 37° C.±0.5° C. and a speed of 100 rpm. 
     
     
       14. The method of  claim 1 , wherein at least 80% of the solid pharmaceutical composition dissolves within 30 minutes when tested according to USP I dissolution test (basket) in 900 mL of acetate buffer at a pH of 4.5 at 37° C.±0.5° C. and a speed of 100 rpm. 
     
     
       15. The method of  claim 1 , wherein at least 80% of the solid pharmaceutical composition dissolves within 30 minutes when tested according to USP I dissolution test (basket) in 900 mL of phosphate buffer at a pH of 6.8 at 37° C.±0.5° C. and a speed of 100 rpm. 
     
     
       16. The method of  claim 1 , wherein the total organics content released from the composition according to the Spill Test is less than 200 ppm. 
     
     
       17. The method of  claim 1 , wherein the total organics content released from the composition according to the Spill Test is less than 150 ppm. 
     
     
       18. The method of  claim 1 , wherein the total organics content released from the composition according to the Spill Test is less than 100 ppm. 
     
     
       19. A method of administering temozolomide comprising orally administering a solution of a temozolomide powder, wherein the temozolomide powder is readily dispersible in an aqueous solution suitable for oral administration and the temozolomide powder comprises:
 (a) granules of temozolomide and one or more emulsifiers, the granules coated with a pH dependent coating composition comprising a pH dependent coating material; and 
 (b) a dispersant, 
 
       wherein at least 80% of the temozolomide powder dissolves within 30 minutes when tested according to USP I dissolution test (basket) in 900 mL of 0.1 N HCl at 37° C.±0.5° C. and a speed of 100 rpm.